The effect of smokeless tobacco (gutkha) was investigated by treating male and female Swiss Albino mice with an aqueous extract of smokeless tobacco (AEST). AEST was administered at a dose of 25 mg kg-1 body weight per day for different time periods (6, 12, 16, and 24 weeks), and control animals were provided only drinking water without AEST for the same period. Control and AEST-treated mice were observed for different oxidative stress parameters, nitric oxide (NO) release, and myeloperoxidase (MPO) release, and they were evaluated for alterations in tumor suppressor and DNA repair responses in the liver and spleen...

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence...

The p21-activated kinase 4 (PAK4) is overexpressed in different cancers and promotes proliferation of cancer cells. Reprogramming of glucose metabolism is found in most cancer cells which in turn supports rapid proliferation. However, the relationship between PAK4 and glucose metabolism in cancer cells has not been explored. In this study, we reported that PAK4 promoted glucose intake, NADPH production and lipid biosynthesis, leading to an increased proliferation of colon cancer cells. Mechanistically, PAK4 interacted with glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway and increased G6PD activity via enhancing Mdm2-mediated p53 ubiquitination degradation...

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53...

Spindle cell lipoma (SCL) is a benign neoplasm of the adipose tissue that may resemble an undifferentiated soft tissue sarcoma (STS). This report describes the histopathological features of 6 SCLs in dogs. All SCLs were located in the subcutis and were composed of bland, occasionally vacuolated spindle cells intermixed with ropey collagen and myxoid matrix. Sudan IV stain performed in 1 case demonstrated the lipid content of vacuoles. Mature adipocytes represented less than 10% of the neoplasm in 3 cases and were absent in the remaining 3...

Liposarcoma, usually arises in deep soft tissues and pleomorphic liposarcoma (PL), is the rarest histopathologic variant. However, 15 cases of entirely dermal PL have been reported. We describe a case of a 79-year-old man who developed a rapidly growing nodule on his thorax. Excisional biopsy was performed and immunohistochemical studies were carried. The lesion was a well-circumscribed dermal nodule composed of multivacuolated pleomorphic lipoblasts and atypical mitotic figures. Neoplastic cells expressed CD10 and resulted negative S100 protein, Melan-A, MITF-1, AE1/AE3, CD4, CD68 (PGM1), retinoblastoma gene family protein, pericentrine and lysozyme...

Exposure to ionizing radiation (IR) could be detrimental to health. Oxidative stress, DNA damage, and inflammation are implicated in radiation damage. Curcumin, a natural polyphenol, has remarkable antioxidant, anti-inflammation and anticarcinogenic properties and is reported to protect cells and organisms against gamma-rays. We have recently enhanced solubility of curcumin via a novel dendrosomal nanoformulation (DNC). The objective of this study was to assess the potential efficacy of this nanoformulation in protecting human peripheral blood mononuclear cells (PBMC) against gamma-radiation...

About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). The persistence of the infection is controlled by several mechanisms including the induction of oxidative stress. HCV relies on this strategy to redirect lipid metabolism machinery and escape immune response. The 3β-hydroxysterol Δ24-reductase (DHCR24) is one of the newly discovered host markers of oxidative stress. This protein, as HCV-induced oxidative stress responsive protein, may play a critical role in the pathogenesis of HCV chronic infection and associated liver diseases, when aberrantly expressed...

Well-differentiated liposarcoma (WDL) can show a morphologic spectrum, including lipoma-like, sclerosing and inflammatory subtypes. It does not metastasize but can dedifferentiate, acquiring metastatic potential. Hibernomas are benign neoplasms that show variable differentiation toward brown fat, and can sometimes occur in the abdomen or retroperitoneum. We illustrate a case of retroperitoneal WDL that showed extensive hibernoma-like morphology, with sheets of multivacuolated adipocytes of varying sizes, with abundant cytoplasm and numerous lipid vacuoles or granular eosinophilic cytoplasm...

BACKGROUND: Lup-20(29)-en-3H-ol (Lupeol), a dietary pentacyclic triterpenoid has been shown to possess multiple medicinal activities including anti-inflammatory, anti-oxidant and anti-carcinogenic effects. Mancozeb is a widely used broad-spectrum fungicide with well-known carcinogenic hazards in rodents. PURPOSE: The present study has been designed to investigate the protective effects of lupeol against mancozeb-induced genotoxicity and apoptosis in cultured human lymphocytes (CHLs)...

OBJECTIVES: The aim of this study was to develop multifunctional fusion proteins for targeting and delivering therapy elements into glioma cells. MATERIALS AND METHODS: Multifunctional fusion proteins were expressed in Escherichia coli and purified using Ni-NTA resin affinity chromatography. Human glioma cells and primary astrocytes were used to analyse their functions. Targeting proteins location to glioma cells was observed by confocal microscopy. Effects of cell viability and proliferation were evaluated using the Cell Counting Kit 8 and colony formation assays...

INTRODUCTION: p53 plays important roles in regulating the metabolic reprogramming of cancer, such as aerobic glycolysis. Oroxylin A is a natural active flavonoid with strong anticancer effects both in vitro and in vivo. METHODS: wt-p53 (MCF-7 and HCT116 cells) cancer cells and p53-null H1299 cancer cells were used. The glucose uptake and lactate production were analyzed using Lactic Acid production Detection kit and the Amplex Red Glucose Assay Kit. Then, the protein levels and RNA levels of p53, mouse double minute 2 (MDM2), and p53-targeted glycolytic enzymes were quantified using Western blotting and quantitative polymerase chain reaction (PCR), respectively...

Autophagy plays a critical role in the progression of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a tumor suppressor, but little is known about its role in NASH. Here, we investigated the role of PTPRO-dependent autophagy in insulin resistance, lipid metabolism, and hepatocarcinogenesis. Wild-type (WT) and ptpro-/- mice were fed a high-fat diet (HFD) for another 16 weeks after diethylnitrosamine (DEN) injection to induce NASH...

Dietary exposure to aflatoxin B1 (AFB1) is detrimental to avian health and leads to major economic losses for the poultry industry. AFB1 is especially hepatotoxic in domestic turkeys (Meleagris gallopavo), since these birds are unable to detoxify AFB1 by glutathione-conjugation. The impacts of AFB1 on the turkey hepatic transcriptome and the potential protection from pretreatment with a Lactobacillus-based probiotic mixture were investigated through RNA-sequencing. Animals were divided into four treatment groups and RNA was subsequently recovered from liver samples...

The tumor suppressor p53 has recently been shown to regulate energy metabolism through multiple mechanisms. However, the in vivo signaling pathways related to p53-mediated metabolic regulation remain largely uncharacterized. By using mice bearing a single amino acid substitution at cysteine residue 305 of mouse double minute 2 (Mdm2(C305F)), which renders Mdm2 deficient in binding ribosomal proteins (RPs) RPL11 and RPL5, we show that the RP-Mdm2-p53 signaling pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis...

Numerous hereditary syndromes caused by mutations in multiple tumor suppressor genes can cause cancers. Germline mutations in PTEN and p53 tumor suppressor cause Cowden syndrome and Li-Fraumeni syndrome, respectively. There exists some phenotypic overlap in these syndromes, and they are associated with high risks of breast cancer. The tumor suppressor protein PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream targets...

Glioblastoma multiforme (GBM) is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM), the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT) technique...

We hypothesized that α-tocopherol, ascorbic acid, and β-carotene, either applied individually or in combination, would modulate redox homeostasis and affect the regulation of genes involved in DNA repair under stress conditions. To test this hypothesis, we analyzed the influence of these vitamins, either supplied individually or in combination, on the plasma lipid peroxide level and the hepatic level of 8-hydroxy-2'-deoxyguanosine in rats. We also evaluated the expression of p53 and Mdm2 protein in the intestinal epithelium, as these proteins are involved in the cellular regulation of DNA damage repair...

Hypoxia-inducible factor 1α (HIF-1α) and p53 are pivotal regulators of tumor growth. Lysophosphatidic acid (LPA) is a lipid mediator that functions as a mitogen by acting through LPA receptors. We have shown previously that LPA stimulates HIF-1α expression in colon cancer cells. To determine the mechanism of HIF-1α induction by LPA, we compared the effect of LPA on HIF-1α in several colon cancer cell lines. LPA transcriptionally induced HIF-1α in colon cancer cells. HIF-1α induction was observed in cells expressing WT p53, where LPA decreased p53 expression...